1. Field of the Invention
The diaromatic substituted compounds (III), the anti-AIDS piperazines (IV), the indoles (V) and the anti-AIDS amines (X) of the invention are useful in the treatment of individuals who are HIV positive whether or not they show AIDS symptoms at the present time.
2. Description of the Related Art
International Publication No. 87/01706, now U.S. Pat. No. 5,175,281, discloses compounds which can be visualized as steroid-piperazine-[substituted aromatic] or steroid-piperazine-[substituted heteroaromatic]. The steroid and piperazine being "connected" via the C.sub.17 side-chain of the steroid.
International Publication No. WO 88/08424 disclosed compounds which can be visualized as
[trolox or indole]-connector-piperazine-[substituted aromatic] PA1 [trolox or indole]-connector-piperazine-[substituted heteroaromatic] PA1 5-methoxy[indol-2-yl]-CO-piperazinyl-[2-quinolinyl] PA1 (non-substituted)-[indol-2-yl]-CO-piperazinyl-(CH.sub.2).sub.n -[optionally substituted) phenyl] The Indian J. Chem. Sect. B, 17B(3), 246-9 (1979) reported on p. 247 that none of the compounds showed any noteworthy (CNS) biological activity. The Indian J. Med. Res., 63(10), 1418-25 (1975) reported some of the compounds they prepared had anti-viral activity against Semliki forest virus (SFV) in mice. One compound, a dihydroisoquinolin was tested and found to be inactive against new castle disease virus in chick embryo. These compounds differ from the claimed compounds in that the claimed compounds require the indole group to be substituted and have a heteroaryl moiety (2-pyridinyl) attached directly to the piperazinyl substituent, not an aryl group (phenyl). PA1 [heteroaryl]-CO-piperazinyl-[quinolinone] PA1 --CO--CH.sub.2 --, PA1 --CH.dbd.CH--CO--; PA1 R.sub.3 is .dbd.O or R.sub.3-1 :R.sub.3-2 where one of R.sub.3-1 and R.sub.3-2 is --H and the other of R.sub.3-1 and R.sub.3-2 is --H or --CH.sub.3, PA1 R.sub.4 is R.sub.4-1 :R.sub.4-2 and R.sub.5 is R.sub.5-1 :R.sub.5-2 where one of R.sub.4-1 and R.sub.4-2 is --H and the other of R.sub.4-1 and R.sub.4-2 is --H or --CH.sub.3, where one of R.sub.5-1 and R.sub.5-2 is --H and the other of R.sub.5-1 and R.sub.5-2 is --H or --CH.sub.3, PA1 (II) R.sub.4 is R.sub.4-3 :R.sub.4-4 and R.sub.5 is R.sub.5-3 :R.sub.5-4 where one of R.sub.4-3 and R.sub.4-4 and one of R.sub.5-3 and R.sub.5-4 are taken together to form --CH.sub.2 -- and the other of R.sub.4-3 and R.sub.4-4, and R.sub.5-3 and R.sub.5-4 are --H, R.sub.2 and R.sub.3 are --H:--H, PA1 (III) R.sub.2 is R.sub.2-5 :R.sub.2-6 and R.sub.5 is R.sub.5-5 :R.sub.5-6 where one of R.sub.2-5 and R.sub.2-6 and one of R.sub.5-5 and R.sub.5-6 are taken together to form --CH.sub.2 --CH.sub.2 --and the other of R.sub.2-5 and R.sub.2-6, and R.sub.5-5 and R.sub.5-6 are --H, and R.sub.3 and R.sub.4 are --H:--H, PA1 (IV) R.sub.3 is R.sub.3-5 :R.sub.3-6 and R.sub.4 is R.sub.4-5 :R.sub.5-6 where one of R.sub.3-5 and R.sub.3-6 and one of R.sub.4-5 and R.sub.4-6 are taken together to form --CH.sub.2 --CH.sub.2 -- and the other of R.sub.3-5 and R.sub.3-6, and R.sub.4-5 and R.sub.4-6 are --H, and R.sub.2 and R.sub.5 are --H:--H, EQU --Y.sub.1 --(CH.sub.2).sub.n11 --Z.sub.2 --(CH.sub.2).sub.n26 --Y.sub.2 --(Z-II) PA1 n.sub.26 is 1 thru 5, PA1 Y.sub.1 is --O--, --S--, PA1 Y.sub.2 is --O--, --S--, PA1 Z.sub.2 is nothing (a bond), --O--, --S--, PA1 R.sub.6 is --N.dbd., PA1 R.sub.7 is --CO--N(R.sub.7-3)(R.sub.7-4) where R.sub.7-3 and R.sub.7-4 are the same or different and are --H or C.sub.1 -C.sub.6 alkyl, PA1 R.sub.8 is --N.dbd., PA1 R.sub.9 is --N.dbd., PA1 R.sub.10 is --N.dbd., PA1 with the proviso that not more than two of R.sub.6, R.sub.8, R.sub.9 and R.sub.10 are --N.dbd.; PA1 Aryl/Heteroaryl is a substituent selected from the group of substituents of formula (1) ##STR7## where X.sub.1 is --H, C.sub.1 -C.sub.6 n-alkyl, X.sub.2 is --H, C.sub.1 -C.sub.6 n-alkyl, PA1 X.sub.3 is C.sub.1 -C.sub.6 alkyl, PA1 and where X.sub.4 and X.sub.5 are taken together with the attached nitrogen atom to form a heterocyclic ring selected from the group consisting of 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl or N-morpholinyl, PA1 and where X.sub.1 and X.sub.2 are as defined above, with the proviso that both X.sub.4 and X.sub.5 are not both --H; PA1 n.sub.2 is 1 thru 3, the X.sub.6 's can be the same or can be different and where when n.sub.2 is 2 and the two X.sub.6 groups are ortho to each other they can be taken together to form --O--CH.sub.2 --O--; with the proviso that if n.sub.2 is 2 or 3, only one of the X.sub.6 's can be a prodrug, PA1 Q.sub.2 is --N.dbd. provided R.sub.1 is not --CH.sub.2 --, PA1 n.sub.7 is 0 thru 2, PA1 X.sub.6 and Q.sub.1 are as defined above; PA1 X.sub.22, X.sub.23 and X.sub.24 are the same or different and are PA1 and where any adjacent two of --O--X.sub.21, X.sub.22, X.sub.23 or X.sub.24 are taken together to form a methylenedioxy group (--O--CH.sub.2 --O--), PA1 Q.sub.1 and .... are as defined above; PA1 X.sub.6 and X.sub.11 are as defined above; PA1 X.sub.8 is --H, C.sub.1 -C.sub.6 alkyl, --CH.sub.2 --.phi., --SO.sub.2 --.phi., --SO.sub.2 --CH.sub.3, --CO--X.sub.8-1 where X.sub.8-1 is C.sub.1 -C.sub.4 alkyl or --.phi., PA1 .... is as defined above; PA1 --SO.sub.2 --, PA1 --CH.dbd.CH--CO--, PA1 --CO--CH.sub.2 --, PA1 R.sub.3 is .dbd.O or R.sub.3-1 :R.sub.3-2 where one of R.sub.3-1 and R.sub.3-2 is --H and other of R.sub.3-1 and R.sub.3-2 is --H or --CH.sub.3, PA1 R.sub.4 is R.sub.4-1 :R.sub.4-2 and R.sub.5 is R.sub.5-1 :R.sub.5-2 where one of R.sub.4-1 and R.sub.4-2 is --H and the other of R.sub.4-1 and R.sub.4-2 is --H or --CH.sub.3, where one of R.sub.5-2 and R.sub.5-2 is --H and the other of R.sub.5-1 and R.sub.5-2 is --H or --CH.sub.3, PA1 (II) R.sub.4 is R.sub.4-3 :R.sub.4-4 and R.sub.5 is R.sub.5-3 :R.sub.5-4 where one of R.sub.4-3 and R.sub.4-4 and one of R.sub.5-3 and R.sub.5-4 are taken together to form --CH.sub.2 -- and the other of R.sub.4-3 and R.sub.4-4, and R.sub.5-3 and R.sub.5-4 are --H, R.sub.2 and R.sub.3 are --H:--H, PA1 (III) R.sub.2 is R.sub.2-5 :R.sub.2-6 and R.sub.5 is R.sub.5-5 :R.sub.5-6 where one of R.sub.2-5 and R.sub.2-6 and one of R.sub.5-5 and R.sub.5-6 are taken together to form --CH.sub.2 --CH.sub.2 -- and the other of R.sub.2-5 and R.sub.2-6, and R.sub.5-5 and R.sub.5-6 are --H, and R.sub.3 and R.sub.4 are --H:--H, PA1 (IV) R.sub.3 is R.sub.3-5 :R.sub.3-6 and R.sub.4 is R.sub.4-5 :R.sub.5-6 where one of R.sub.3-5 and R.sub.3-6 and one of R.sub.4-5 and R.sub.4-6 are taken together to form --CH.sub.2 --CH.sub.2 -- and the other of R.sub.3-5 and R.sub.3-6, and R.sub.4-5 and R.sub.4-6 are --H, and R.sub.2 and R.sub.5 are --H:--H, EQU --Y.sub.1 --(CH.sub.2).sub.n11 --Z.sub.2 --(CH.sub.2).sub.n26 --Y.sub.2 --(Z-II) PA1 n.sub.26 is 1 thru 5, PA1 Y.sub.1 is --O--, --S--, PA1 Y.sub.2 is --O--, --S--, PA1 Z.sub.2 is nothing (a bond), --O--, --S--, PA1 R.sub.6 is --N.dbd., PA1 R.sub.7A is --S--R.sub.7A-1 where R.sub.7A-1 is C.sub.1 -C.sub.6 alkyl, PA1 --CO--R.sub.7 A.sub.-11 where R.sub.7 A.sub.-11 is --H, PA1 and where R.sub.7A-6 is --H, PA1 R.sub.8 is --N.dbd., --CR.sub.8-1 .dbd. where R.sub.8-1 is --H, --F, --Cl, --Br, --CF.sub.3, --NO.sub.2, --COCF.sub.3, PA1 R.sub.9 is --N.dbd. or --CR.sub.9-1 .dbd. where R.sub.9-1 is --H, --F, --Cl, --Br, --NO.sub.2, --COCF.sub.3, PA1 R.sub.10 is --N.dbd. or --CR.sub.10-1 is --H, --F, --Cl, --Br, --CF.sub.3, --NO.sub.2, --COCF.sub.3, PA1 with the proviso that not more than two of R.sub.6, R.sub.8, R.sub.9 and R.sub.10 are --N.dbd.; PA1 where .... is a single or double bond; PA1 Q.sub.1 is --NX.sub.11 where X.sub.11 is --H, --SO.sub.2 --.phi., --SO.sub.2 --CH.sub.3, --CO--X.sub.11-1 where X.sub.11-1 is C.sub.1 -C.sub.4 alkyl, --CF.sub.3 or --.phi.; PA1 X.sub.17 is --H or --CH.sub.3 ; PA1 X.sub.18 is --H or --CH.sub.3 ; PA1 X.sub.19 is --H or --CH.sub.3 ; PA1 X.sub.20 is --H, C.sub.1 -C.sub.4 alkyl, --CO--(C.sub.1 -C.sub.4 alkyl), --CH.sub.2 --.phi., --CO--.phi. or --prodrug where prodrug is --PO.sub.2 --O.sup.- cation.sup.+, PA1 R.sub.6 is PA1 R.sub.7B is --CO--R.sub.7B-11 where R.sub.7 B.sub.-11 is --H, PA1 --S--R.sub.7B-1 where R.sub.7B-1 is C.sub.1 -C.sub.6 alkyl, PA1 --O--R.sub.7B-2 where R.sub.7B-2 is C.sub.1 -C.sub.6 alkyl, PA1 --C(R.sub.7B-15)(R.sub.7B-16)--(R.sub.7B-17) where R.sub.7B-15 and R.sub.7B-16 are --H, or C.sub.1 -C.sub.3 alkyl and R.sub.7B-17 is C.sub.2 -C.sub.5 alkenyl containing 1 or 2 double bonds or C.sub.2 -C.sub.5 alkynyl containing 1 triple bond, PA1 R.sub.8 is --N.dbd., --CH.dbd. PA1 R.sub.9 is --N.dbd., --CH.dbd. PA1 R.sub.10 is --N.dbd., --CH.dbd.
in particular see the compounds of formula (III). None of those compounds were disclosed as having the utility set forth in this invention. In U.S. Pat. No. 5,120,843 it was disclosed that the compounds of formula (I) of International Publication No. WO 88/08424 were useful against AIDS. The anti-AIDS piperazines (IV) of the present invention are a few particular piperazines previously generically disclosed in International Publication No. WO 88/08424. The indoles compounds (V) of the present invention have been previously generically disclosed in International Publication No. WO 88/08424, see the bicyclic compounds of formula (III) therein.
U.S. Pat. No. 4,728,650 (Kuraray I) discloses hydroxy-trolox compounds similar to the compounds of formula (III) of International Publication No. WO 88/08424. WO 87/05020 (Kuraray II) discloses additional compounds of the same type.
An estimated one to one and one-half million people in the United States are infected with a human retrovirus, the human immunodeficiency virus type I (HIV-1) which is the etiological agent of acquired immunodeficiency syndrome, AIDS, see Science, 661-662 (1986). Of those infected, an estimated two hundred and fifty thousands people will develop AIDS in the next five years, see Science, 1352-1357 (1985). On Mar. 20, 1987, the FDA approved the use of the compound, AZT (zidovudine), to treat AIDS patients with a recent initial episode of pneumocystis carinii pneumonia, AIDS patients with conditions other than pneumocystis carinii pneumonia or patients infected with the virus with an absolute CD4 lymphocyte count of less than 200/mm.sup.3 in the peripheral blood. AZT is a known inhibitor of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication.
U.S. Pat. No. 4,724,232 claims a method of treating humans having acquired immunodeficiency syndrome utilizing 3'-azido-3'-deoxy-thymidine (azidothymidine, AZT).
It is known in the art that certain antibiotics and polyanionic dyes inhibit retrovirus reverse transcriptase.
Many publications have reported the ability of various sulfated compounds to inhibit virus replication, including HIV.
Nature 343, 470 (1990) and Science 250, 1411 (1990) discloses potent benzodiazepin type reverse transcriptase inhibitors. The compounds of the present invention are not benzodiazepin type compounds.
Following the discovery of the anti-HIV activity of AZT, much effort has been focused on a wide variety of other dideoxynucleoside analogues in the search for superior agents. In the case of the 2',3'-dideoxy series, ddC and ddI have shown potent activity against HIV in vitro and have been evaluated in clinical trials, see Drug News & Perspectives, 5(3) 153-169 (1992) in particular page 160. The FDA has approved ddI for the treatment of HIV-1 infections in adults and pediatrics patients who are intolerant to, or whose health has significantly deteriorated while on, AZT treatment, see AIDS research and Human Retroviruses, 8(6), 963-990, (1992) in particular page 966.
U.S. Pat. Nos. 3,146,234 and 3,188,313 disclose compounds of the general formula EQU [substituted indol-2-yl]-(CH.sub.2).sub.n -[piperazinyl type]-[aryl/heteroaryl]
The diaromatic substituted compounds (III) and the anti-AIDS piperazines (IV) of the present invention differ from the prior art compounds in that for the heteroaryl group they require substitution on the heteroaryl group and for the aryl group they require the substitution to be a group different than that of the groups in U.S. Pat. No. 3,188,313.
U.S. Pat. Nos. 3,472,855 and 3,562,278 disclose 3-indolinyl compounds which are useful as psychomotor depressants. The 2-indolinyl compounds of the present invention are useful for a totally different purpose, inhibition of HIV-RT and treatment of AIDS.
U.S. Pat. No. 3,362,956 discloses compounds of the general formula EQU [3-quinolyl]-(CH.sub.2).sub.n -[piperazinyl type]-[pyridinyl/phenyl].
The diaromatic substituted compounds (III) of the present invention differ from the prior art compounds in that they do not include 3-quinolyl type compounds.
U.S. Pat. No. 3,472,854 discloses compounds of the general formula EQU [2-benzimidazolyl]-(CH.sub.2).sub.n -[piperazinyl type]-[pyridinyl/phenyl].
The diaromatic substituted compounds (III) of the present invention differ from the prior art compounds in that they do not have a methylene linker, --(CH.sub.2).sub.n -, when the heteroaryl group is 2-benzimidazolyl.
U.S. Pat. No. 3,491,098 discloses compounds of the general formula EQU [4(5)-imidazolyl]-(CH.sub.2).sub.n -[piperazinyl type]-[pyridinyl/phenyl].
The diaromatic substituted compounds (III) of the present invention differ from the prior art compounds in that they require the substitution on --.phi. to be a group different than that of the group in the U.S. Pat. No. 3,491,098.
U.S. Pat. No. 3,511,841 discloses compounds of the general formula EQU [azaindolyl]-(CH.sub.2).sub.n -[piperazinyl type]-[pyridinyl/phenyl] EQU [azaindolyl]-CO-[piperazinyl type]-[pyridinyl/phenyl]
The diaromatic substituted compounds (III) of the present invention differ from the prior art compounds in that they require the substitution on --.phi. to be a group different than that of the group in U.S. Pat. No. 3,188,313.
U.S. Pat. No. 4,302,589 discloses 3-indolinyl compounds with a methyl group at the C.sub.2 position of the indole and an ethyl bridge between the indole and piperazine which are useful as anti-psychotics. The 2-indolinyl compounds of the present invention are useful for a totally different purpose, inhibition of HIV-RT and treatment of AIDS.
European patent publication 345,808 discloses 3-indolinyl-piperazinyl-[substituted 2-pyridinyl] compounds (example 66) which are useful as anti-depressants. The 2-indolinyl compounds of the present invention are useful for a totally different purpose, inhibition of HIV-RT and treatment of AIDS.
There are a number of other chemically unrelated compounds which have been reported to inhibit HIV and/or be useful in the treatment of AIDS.
EP 0 154 969 and U.S. Pat. No. 4,613,598 disclose compounds of the formula EQU [substituted]-aromatic-CO--(CH.sub.2).sub.3-5 -[piperazinyl]-Ar EQU [substituted]-aromatic-CHOH--(CH.sub.2).sub.3-5 -[piperazinyl]-Ar
where Ar is pyridinyl, --.phi. or substituted --.phi. which have the ability to lower blood pressure.
VINITI, 3979-82 (1982) in Russian and Chem. Abst. 100(7) 51549b (1984) discloses a compound which can be represented as
which differes from the claimed compounds in that none of the claimed compounds have quinoline structure or any bicyclic structure attached to the piperazinyl moiety.
JP 01132579 (1987) discloses compounds which can be represented as (optionally substituted)-[indol-2-yl]-CO-piperazinyl-(CH.sub.2).sub.n -[pyridinyl] which have very strong blood platelet agglutination inhibiting activity where n is 1-5 which differs from the claimed compounds in that the claimed compounds do not permit any linking group between the piperazinyl moiety and the phenyl or pyridinyl substitutent.
Indian J. Chem. Sect. B, 17B(3), 246-9 (1979) and Indian J. Med. Res., 63(10), 1418-25 (1975) disclose compounds which can be represented as
International Publication EP 370 381 A2, published 5 May 90 discloses compounds which can be represented as
where heteroaryl includes 2-indolyl which differ from the claimed compounds in that none of the claimed compounds have quinoline structure or any bicyclic structure attached to the piperazinyl moiety. The disclosed compounds possess cardiotonic and hypotensiv activities and the capability of reducing the heart rate.
U.S. Pat. Nos. 5,032,598 and 5,215,989 disclose anti-arrhythmic compounds of the formula EQU R.sup.2 R.sup.3 Ar-[B]-X-Q-Y-R.sup.1
which if the appropriate substitutents were selected generically encompasses the diaromatic substituted compounds of formula (III), anti-AIDS piperazines (IV) and the indoles compounds (V) of the present invention.